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mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation

William Damsky1, Goran Micevic2, Katrina Meeth3

  • 1Department of Dermatology, Yale University, New Haven, CT 06510, USA.

Cancer Cell
|January 14, 2015
PubMed

Insights

BRAF V600E mutation drives nevus development. Loss of CDKN2A and STK11 cooperatively activates mTORC1/2, promoting rapid melanoma formation from benign nevi.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRAF V600E mutation initiates benign melanocytic nevi but can drive melanoma.
  • CDKN2A loss in BRAF V600E melanocytes leads to rare melanoma after growth arrest.
  • MicroRNA miR-99/100 inhibits melanoma progression by downregulating mTOR and IGF1R.

Purpose of the Study:

  • To investigate the cooperative roles of CDKN2A and STK11 (LKB1) loss in BRAF-induced melanomagenesis.
  • To elucidate the involvement of mTORC1 and mTORC2 signaling pathways in melanoma development.

Main Methods:

  • Utilized a mouse model with BRAF V600E-mutated melanocytes.
  • Genetically inactivated CDKN2A and/or STK11 (LKB1) in these melanocytes.
  • Analyzed mTORC1, mTORC2, and Akt activation in resulting melanocytic neoplasms.

Main Results:

  • STK11 loss alone abrogated growth arrest but was insufficient for melanoma.
  • CDKN2A loss correlated with mTORC2/Akt activation.
  • Simultaneous inactivation of CDKN2A and STK11 activated both mTORC1 and mTORC2/Akt, leading to rapid melanoma formation.

Conclusions:

  • Co-activation of mTORC1 and mTORC2 pathways is essential for BRAF-driven melanoma.
  • CDKN2A and STK11 inactivation cooperate to promote melanoma by activating both mTORC1 and mTORC2/Akt signaling.

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